Patients with Alzheimer's disease (AD) are typically presented to a clinician by a relative who has observed a decline in memory with or without a change in other cognitive abilities such as declines in executive function, difficulty in word finding or visuo-spatial impairment such as an inability to draw complex geometric structures or becoming lost in familiar places. Neuropathological analysis of brains from patients with AD has revealed extensive neuronal and synaptic loss in select brain regions, neurofibrillary tangles, and the deposition of β-amyloid (Aβ) polypeptides in the form of senile plaques throughout the hippocampus and neocortex.
Aβ polypeptides are produced from the amyloid precursor protein (APP) through the combined proteolytic actions of β- and γ-secretases and are then secreted into the extracellular milieu. Biochemical and immunocytochemical studies have revealed that the Aβ polypeptides deposited in brains from patients with AD have substantial amino- and carboxyl-terminal heterogeneity and can contain from 39 to 43 amino acid residues, with β-amyloid 1-40 (Aβ40) and 1-42 (Aβ42) being the most predominant. By comparing signals obtained using antibodies directed at the amino terminus of Aβ with those obtained by capturing the peptide from an internal epitope, it was found that virtually all Aβ42 in AD brain is amino-terminally modified and/or truncated.